Malignant brain tumors, both metastatic and primary occur frequently, and only palliative therapy is available at present. CNS tumors are particularly devastating to the quality of life of patients, as they frequently result in severe and debilitating neurological complications including headache, paralysis, seizures, and impaired cognition. The applicants have performed preliminary experiments in a mouse intracranial melanoma model, that demonstrate the viability of a tumor therapy approach based on the use of replication competent neuro-attenuated Herpes Simplex Virus-1 (HSV-1) mutants. The rationale for this approach is that these genetically mutant viruses cannot replicate within the generally post mitotic cells of the nervous system, yet do replicate in cancer cells, which are mitotically active. Thus, they can be used to selectively lyse cancer cells within the CNS. The applicants have developed a straightforward, reproducible, clinically relevant model in which to study brain tumor therapy. The presence, progression, or regression of tumors can be assessed by non-invasive magnetic resonance imaging, and histology, immunohistochemistry, RNA in situ hybridization, and viral titration studies allow detailed examination of viral induced effects on tumor and brain. Outcome experiments indicate that HSV-1 mutant 1716 can slow progression of pre-formed tumors, and even lead to complete regression of tumors in some animals. No deaths or untoward effects attributable to HSV-1 have been observed. The experiments outlined in this proposal will critically examine several important aspects of the tumor-virus-host relationship that is occurring. Specifically, the applicants will i) extend their preliminary data to other promising HSV-1 mutants and examine the viral and tumor cell factors that influence therapy; ii) examine the role of primary and secondary antiviral immunity in this model; iii) explore strategies to augment the effectiveness of HSV-1 based tumor therapy by combining viral therapy with ganciclovir treatment, and engineering HSV-1 mutants that will express biological response modifiers, such as IL-2, specifically within tumor cells.